This application claims priority under 35 U.S.C. 119 of GB 9912413.3, filed May 28, 1999.
This invention relates to pharmaceutically useful compounds, in particular compounds that bind to opiate receptors (e.g. mu, kappa and delta opioid receptors).
Compounds that bind to such receptors are likely to be useful in the treatment of diseases mediated by opiate receptors, for example irritable bowel syndrome; constipation; nausea; vomiting; and pruritic dermatoses, such as allergic dermatitis and atopy in animals and humans. Compounds that bind to opiate receptors have also been indicated in the treatment of eating disorders, opiate overdoses, depression, smoking and alcohol addiction, sexual dysfunction, shock, stroke, spinal damage and head trauma.
There is a particular need for an improved treatment of itching. Itching, or pruritus, is a common dermatological symptom that can give rise to considerable distress in both humans and animals. Pruritus is often associated with inflammatory skin diseases which may be caused by hypersensitivity reactions, including reactions to insect bites, such as flea bites, and to environmental allergens, such as house dust mite or pollen; by bacterial and fungal infections of the skin; or by ectoparasite infections.
Existing treatments that have been employed in the treatment of pruritus include the use of corticosteroids and antihistamines. However, both of these treatments are known to have undesirable side effects. Other therapies that have been employed include the use of essential fatty acid dietary supplements, though these have the disadvantages of being slow to act, and of offering only limited efficacy against allergic dermatitis. A variety of emollients such as soft paraffin, glycerine and lanolin are also employed, but with limited success.
Thus, there is a continuing need for alternative and/or improved treatments of pruritus.
Certain 4-arylpiperidine-based compounds are disclosed in inter alia European patent applications EP 287339, EP 506468, EP 506478 and J. Med. Chem. 1993, 36, 2833-2850 as opioid antagonists. In addition, International Patent Application WO 95/15327 discloses azabicycloalkane derivatives useful as neuroleptic agents.
According to the invention there is provided compounds of formula I: 
wherein Het1 represents a 5-, 6- or 7-membered heterocyclic ring containing at least one nitrogen atom, and optionally one or more heteroatoms selected from oxygen or sulfur, and which heterocyclic ring is fully saturated, partially unsaturated or aromatic in character;
T represents one or more optional substituents selected from H, halo, OH, xe2x95x90O, C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl (which latter three groups are optionally substituted by one or more halo atoms), aryl(C1-6)alkyl (the aryl part of which is optionally substituted by one or more substituents selected from halo, C1-4 alkyl and C1-4 alkoxy (which latter two groups are optionally substituted by one or more halo atoms)), xe2x80x94N(R4a)(R5), xe2x80x94N(R4b)S(O)mR6, xe2x80x94N(R4c)C(O)R7a and xe2x80x94N(R4d)C(O)OR7b, provided that when Het1 contains less than three C-atoms (i.e. where the only two C-atoms are those provided by the fused benzene ring) and at least one heteroatom selected from oxygen and sulfur, then T does not represent halo or C1-6 alkoxy (which latter group is optionally substituted by one or more halo atoms);
R4a to R4d and R5 independently represent H, C1-6 alkyl (which latter group is optionally substituted by one or more halo atoms), or R4a and R5, together with the nitrogen atom to which they are attached, form a 4- to 6-membered heterocyclic ring (which ring is optionally substituted by one or more substituents selected from C1-4 alkyl, C1-4 alkoxy, OH, xe2x95x90O, nitro, amino or halo);
R6 represents C1-6 alkyl or aryl, which two groups are optionally substituted by one or more substituents selected from halo, C1-4 alkyl or nitro;
R7a and R7b independently represent C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl, aryl (which four groups are optionally substituted by one or more substituents selected from halo, C1-4 alkyl or nitro), or R7a represents H;
m is 0, 1 or 2;
R1 and R2 are each independently H or C1-4 alkyl;
R3 represents aryl (optionally substituted by one or more substituents selected from OH, nitro, halo, CN, CH2CN, CONH2, C1-4 alkyl, C1-4 alkoxy, C1-5 alkanoyl (which latter three groups are optionally substituted by one or more halo atoms) and xe2x80x94N(R8a)(R8b)), C1-10 alkyl, C3-10 alkenyl or C3-10 alkynyl wherein said alkyl, alkenyl or alkynyl groups are optionally substituted and/or terminated by one or more substituents selected from OR8c, S(O)nR8d, CN, halo, C1-6 alkoxy carbonyl, C2-6 alkanoyl, C2-6 alkanoyloxy, C3-8 cycloalkyl, C4-9 cycloalkanoyl, N(R9a)S(O)2R10, Het2, aryl, adamantyl (which latter two groups are optionally substituted by one or more substituents selected from OH, nitro, amino, halo, CN, CH2CN, CONH2, C1-4 alkyl, C1-4 alkoxy and C1-5 alkanoyl (which latter three groups are optionally substituted by one or more halo atoms)), or xe2x80x94Wxe2x80x94A1xe2x80x94N(R9b)(R9c);
n is 0, 1 or 2;
W represents a single bond, C(O) or S(O)p;
A1 represents a single bond or C1-10 alkylene; provided that when both W and A1 represent single bonds, then the group xe2x80x94N(R9b)(R9c) is not directly attached to an unsaturated carbon atom;
p is 0, 1 or 2;
R8a to R8d each independently represent H, C1-10 alkyl, C3-10 alkenyl, C3-10 alkynyl, C3-8 cycloalkyl, C1-4 alkylphenyl, aryl (which latter six groups are optionally substituted by or one or more substituents selected from OH, nitro, amino, halo, CN, CH2CN, CONH2, C1-4 alkyl, C1-4 alkoxy and C1-5 alkanoyl (which latter three groups are optionally substituted by one or more halo atoms)) or Het3;
provided that R8d does not represent H when n represents 1 or 2;
R9a to R9c each independently represent H, C1-10 alkyl, C3-10 alkenyl, C3-10 alkynyl, C3-8 cycloalkyl, C1-4 alkylphenyl, aryl (which latter six groups are optionally substituted by or one or more substituents selected from OH, nitro, amino, halo, CN, CH2CN, CONH2, C1-4 alkyl, C1-4 alkoxy and C1-5 alkanoyl (which latter three groups are optionally substituted by one or more halo atoms)), Het4, or R9b and R9c together represent unbranched C2-6 alkylene which alkylene group is optionally interrupted by O, S and/or an N(R11) group and is optionally substituted by one or more C1-4 alkyl groups;
R10 represents C1-6 alkyl, C3-8 cycloalkyl, C1-4 alkylphenyl or aryl, which four groups are optionally substituted by or one or more substituents selected from C1-4 alkyl, C1-4 alkoxy, OH, nitro, amino or halo;
R11 represents H, C1-6 alkyl, C3-8 cycloalkyl, A2xe2x80x94(C3-8 cycloalkyl) or
A2-aryl;
A2 represents C1-6 alkylene;
Het2, Het3 and Het4 independently represent 3- to 8-membered heterocyclic groups, which groups contain at least one heteroatom selected from oxygen, sulfur and/or nitrogen, which groups are optionally fused to a benzene ring, and which groups are optionally substituted in the heterocyclic and/or fused benzene ring part by one or more substituents selected from OH, xe2x95x90O, nitro, amino, halo, CN, aryl, C1-4 alkyl, C1-4 alkoxy and C1-5 alkanoyl (which latter three groups are optionally substituted by one or more halo atoms);
X represents one or two optional substituents on the benzene ring, which substituents are selected from halo, C1-4 alkyl, C1-4 alkoxy (which latter two groups are optionally substituted by one or more halo atoms);
or pharmaceutically, or veterinarily, acceptable derivatives thereof;
which compounds are referred to together hereinafter as xe2x80x9cthe compounds of the invention.xe2x80x9d
In the definitions used herein, alkyl, alkylene, alkoxy, alkoxy carbonyl, alkanoyl, alkanoyloxy, alkenyl, alkynyl and the alkyl parts of alkylphenyl and aryl alkoxy groups may, when there is a sufficient number of carbon atoms, be straight or branched-chain and/or optionally interrupted by one or more oxygen and/or sulfur atom(s). The term halo includes fluoro, chloro, bromo or iodo. The term xe2x80x9carylxe2x80x9d includes optionally substituted phenyl, naphthyl and the like, and xe2x80x9caryloxyxe2x80x9d includes optionally substituted phenoxy and naphthyloxy and the like. Unless otherwise specified, aryl and aryloxy groups are optionally substituted by one or more (e.g. one to three) substituents selected from OH, nitro, amino, halo, CN, CH2CN, CONH2, C1-4 alkyl, C1-4 alkoxy C1-4 alkoxy carbonyl and C1-5 alkanoyl (which latter four groups are optionally substituted by one or more halo atoms).
The heterocyclic rings that Het2, Het3 and Het4 represent and that N(R4a)(R5) may represent, may be fully saturated, partially unsaturated and/or wholly or partially aromatic in character. Specific rings that may be mentioned include: for Het2, dioxane, dioxolane, morpholine, piperidine, perhydroazepine, tetrahydrofuran, tetrahydropyran or tetrazole.
For the avoidance of doubt, when heterocyclic groups (i.e. Het2, Het3, Het4 and some definitions of N(R4a)(R5)) are at least part-saturated, possible points of substitution include the atom (e.g. the carbon atom) at the point of attachment of the heterocyclic group to the rest of the molecule. Het (Het2, Het3 and Het4) groups may also be attached to the rest of the molecule via a heteroatom.
The piperidine moiety in compounds of formula I may be in N-oxidised form. Sulfur atoms that may interrupt (e.g. alkyl) substituents in compounds of formula I may be present in oxidised form (e.g. as sulfoxides or sulfones). All heterocyclic groups (i.e. Het1, Het2, Het3, Het4 and some definitions of N(R4)(R5)) may also be in N- or S-oxidized forms.
The term xe2x80x9cpharmaceutically, or veterinarily, acceptable derivativesxe2x80x9d includes non-toxic salts. Salts which may be mentioned include: acid addition salts, for example, salts formed with sulfuric, hydrochloric, hydrobromic, phosphoric, hydroiodic, sulfamic, organo-sulfonic, citric, carboxylic (e.g. acetic, benzoic, etc.), maleic, malic, succiric, tartaric, cinnamic, ascorbic and related acids; base addition salts; salts formed with bases, for example, the sodium, potassium and C1-4 alkyl ammonium salts.
The compounds of the invention may also be in the form of quaternary ammonium salts, e.g. at the piperidine moiety, which salts may be formed by reaction with a variety of alkylating agents, such as an alkyl halide or an ester of sulfuric, or an aromatic sulfonic, acid.
The compounds of the invention may exhibit tautomerism. All tautomeric forms of the compounds of formula I are included within the scope of the invention.
The compounds of the invention contain one or more asymmetric centres and thus they can exist as enantiomers and diastereomers. Diastereoisomers may be separated using conventional techniques e.g. by fractional crystallisation or chromatography. The various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional techniques e.g. fractional crystallisation or HPLC. The desired optical isomers may be prepared by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation. Alternatively, the desired optical isomers may be prepared by resolution, either by HPLC of the racemate using a suitable chiral support or, where appropriate, by fractional crystallisation of the diastereoisomeric salts formed by reaction of the racemate with a suitable optically active acid or base. The invention includes the use of both the separated individual isomers as well as mixtures of isomers.
Also included within the scope of the invention are radiolabelled derivatives of compounds of formula I which are suitable for biological studies.
Preferred compounds of the invention include those wherein:
Het1 is fused at the 3,4-position on the benzene ring relative to the piperidine ring;
R1 represents C1-2 alkyl;
R2 represents H or C1-2 alkyl;
R3 represents saturated C1-10 (e.g. C1-8) alkyl, optionally interrupted by oxygen and/or optionally substituted by one or more substituents selected from OR8c, CN, halo, C1-6 alkoxy carbonyl, C2-6 alkanoyl, C2-6 alkanoyloxy, C3-8 cycloalkyl, C4-9 cycloalkanoyl, N(R9a)S(O)2R10, Het2, phenyl (which latter group is optionally substituted by one or more substituents selected from OH, C1-4 alkyl, C1-4 alkoxy, C2-5 alkanoyl, halo, nitro, amino, CN, CH2CN, CONH2 and CF3), and/or xe2x80x94Wxe2x80x94A1xe2x80x94N(R9b)(R9c); R8c represents H, C1-6 alkyl, C3-8 cycloalkyl, phenyl or C1-4 alkylphenyl (which latter two groups are optionally substituted by one or more substituents selected from OH, C1-4 alkyl, C1-4 alkoxy, C2-5 alkanoyl, halo, nitro, amino, CN, CH2CN, CONH2 and CF3);
R9a to R9c each independently represent H, C1-4 alkyl, C1-2 alkylphenyl or aryl (which latter two groups are optionally substituted by or one or more substituents selected from C1-2 alkyl, C1-2 alkoxy, OH or halo);
R10 represents C1-4 alkyl or aryl, which two groups are optionally substituted by or one or more substituents selected from C1-2 alkyl, C1-2 alkoxy, nitro or halo;
W represents C(O) or S(O)2;
A1 represents a single bond or C1-4 alkylene;
T represents H, OH, C1-6 alkyl (optionally substituted with one or more halo atoms), C1-4 alkoxy, C4-6 cycloalkyl, aryl(C1-3)alkyl, xe2x80x94NH(R5) or xe2x80x94N(H)S(O)2R6;
R5 represents H or C1-2 alkyl;
R6 represents C1-2 alkyl.
More preferred compounds of the invention include those wherein:
Het1 represents a 5- or 6-membered heterocyclic ring, optionally containing an NH group;
R1 represents methyl;
R2 represents H or methyl;
R3 represents saturated C1-7 alkyl, optionally substituted by one or more substituents selected from OR8c, CN, halo and phenyl (which latter group is optionally substituted by one or more C1-4 alkyl groups);
R8c represents H, C1-4 alkyl, phenyl or C1-4 alkylphenyl (which latter two groups are optionally substituted by one or more C1-4 alkyl groups);
T represents H, NH2, C4-6 cycloalkyl or C1-6 alkyl (which latter group is optionally substituted by one or more halo atoms);
X represents halo, particularly fluoro.
Still further preferred compounds of the invention include those wherein: Het1, together with the benzene ring to which it is fused, represents an aromatic heterocycle, particularly a benzimidazole, benzotriazole, benzoxadiazole, benzoxazole, benzothiazole, cinnoline, indole, isoquinoline, phthalazine, quinazoline, quinoline or quinoxaline group;
T represents H, CH3, CHF2, CF3, ethyl, isopropyl, C4-5 cycloalkyl or NH2;
R1 and R2 both represent methyl groups in the mutually trans configuration;
R3 represents saturated C1-7 alkyl, optionally substituted by one or more substituents selected from OR8c and phenyl, (which latter group is optionally substituted by one or more C1-2 alkyl groups);
R8c represents C2-4 alkyl, phenyl or C1-2 alkylphenyl.
Particularly preferred compounds of the invention include those wherein:
Het1, together with the benzene ring to which it is fused, represents a benzirnidazole group;
T represents H, CHF2 or CF3.
Preferred compounds of the invention include the compounds of the Examples described hereinafter.
According to a further aspect of the invention there is provided processes for the preparation of compounds of the invention, as illustrated below.
The following processes are illustrative of the general synthetic procedures which may be adopted in order to obtain the compounds of the invention.
1. Compounds of formula I wherein Het1 represents the 5-membered ring of a benzimidazole, optionally substituted in the 2-position by C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl (which three groups are optionally substituted by one or more halo atoms) or aryl(C1-6)alkyl (the aryl part of which is optionally substituted by one or more substituents selected from halo, C1-6 alkyl and C1-6 alkoxy, which latter two groups are optionally substituted by one or more halo atoms), may be prepared by reaction of a corresponding compound of formula II, 
wherein R1, R2, R3 and X are as hereinbefore defined, with a compound of formula III,
Taxe2x80x94C(OR12)3xe2x80x83xe2x80x83III,
wherein Ta represents H, C1-6 alkyl C1-6 alkoxy, C3-6 cycloalkyl (which latter three groups are optionally substituted by one or more halo atoms) or aryl(C1-6)alkyl (the aryl group of which is optionally substituted by one or more substituents selected from halo, C1-6 alkyl and C1-6 alkoxy, which latter two groups are optionally substituted by one or more halo atoms) and R12 represents C1-2 alkyl, for example at between room and reflux temperature in the presence of a suitable solvent and/or acidic catalyst (e.g. acetic acid).
Compounds of formula II may be prepared by reduction of a corresponding nitroaniline of formula IV, 
wherein R1, R2, R3 and X are as hereinbefore defined, for example by hydrogenation under standard catalytic conditions, or in the presence of a suitable reducing agent (e.g. finely divided metallic iron combined with calcium chloride) and an appropriate solvent (e.g. water or a water/alcohol mixture).
Compounds of formula IV may be prepared by nitration of a corresponding aniline of formula V, 
wherein R1, R2, R3 and X are as hereinbefore defined, under conditions known to those in the art, for example by reaction with a suitable nitronium salt (e.g. nitronium tetrafluoroborate) in the presence of an appropriate solvent (e.g. acetonitrile).
Compounds of formula V may be prepared by hydrolysis of a corresponding compound of formula VI, 
wherein R1, R2, R3 and X are as hereinbefore defined, under conditions known to those skilled in the art, for example by reaction at between room and reflux temperature with a suitable strong acid (e.g. HCl) and (optionally) an appropriate co-solvent (e.g. dioxan).
Compounds of formula VI may be prepared by rearrangement of a corresponding compound of formula VII, 
wherein R1, R2, R3 and X are as hereinbefore defined, for example at between 25 and 200xc2x0 C. in the presence of a suitable strong base (e.g. sodium hydride) and an appropriate solvent (e.g. 1-methyl-2-pyrrolidinone or N,N-dimethylformamide).
Compounds of formula VII may be prepared by reaction of a corresponding compound of formula VIII, 
wherein R1, R2, R3 and X are as hereinbefore defined, with a compound of formula IX,
L1xe2x80x94C(CH3)2C(O)NH2xe2x80x83xe2x80x83IX
wherein L1 is a suitable leaving group (e.g. halo, arene sulfonate, alkane sulfonate or perfluoroalkane sulfonate), for example at between room and reflux temperature in the presence of a suitable base (e.g. caesium carbonate in combination with sodium hydride) and an appropriate solvent (e.g. dioxan).
Compounds of formula VIII may be prepared by reaction of a corresponding compound of formula X, 
wherein R1, R2 and X are as hereinbefore defined, with a compound of formula XI,
R3L1xe2x80x83xe2x80x83XI
wherein R3 and L1 are as hereinbefore defined, for example under conditions known to those skilled in the art, which include, for example, alkylation at between room temperature and reflux temperature in the presence of a reaction-inert organic solvent (e.g. N,N-dimethylformamide) and a suitable base (e.g. NaHCO3), and arylation at between room temperature and reflux temperature in the presence of a suitable catalyst system (e.g. tris(dibenzylideneacetone)palladium(O) combined with tri-o-tolylphosphine), an appropriate strong base (e.g. sodium tert-butoxide) is and a reaction-inert solvent (e.g. toluene).
2. Compounds of formula I wherein Het1 represents the 5-membered ring of a benzimidazole, optionally substituted in the 2-position by Ta, wherein Ta is as hereinbefore defined provided that it does not represent C1-6 alkoxy or C1-6 haloalkoxy, may be prepared by reaction of a corresponding compound of formula II, as hereinbefore defined, with a compound of formula XII,
Taxe2x80x94C(O)OHxe2x80x83xe2x80x83XII
or a suitable (e.g. carboxylic acid) derivative thereof (e.g. an acid halide or an anhydride), wherein Ta is as hereinbefore defined provided that it does not represent C1-6 alkoxy or C1-6 haloalkoxy, for example at between room temperature and 250xc2x0 C.
3. Compounds of formula I wherein Het1 represents the 5-membered ring of a benzimidazole, optionally substituted in the 2-position by a hydroxy group, may be prepared by reaction of a corresponding compound of formula II, as hereinbefore defined, with a suitable derivative of carbonic acid (e.g. urea), for example at between room and reflux temperature in the presence of a suitable solvent (e.g. N,N-dimethylformamide).
4. Compounds of formula I wherein Het1 represents the 5-membered ring of a benzimidazole, substituted in the 2-position by a N(H)S(O)2R6 group, wherein R6 is as hereinbefore defined, may be prepared by reaction of a corresponding compound of formula II, as hereinbefore defined, with a compound of formula XIII,
(L2)2Cxe2x95x90NS(O)2R6xe2x80x83xe2x80x83XIII
wherein L2 represents a leaving group (such as halo) and R6 is as hereinbefore defined, for example at between room and reflux temperature in the presence of a reaction-inert solvent (e.g. toluene).
5. Compounds of formula I wherein Het1 represents the 5-membered ring of a benzimidazole, substituted in the 2-position by an amino group, may be prepared by hydrolysis of a corresponding compound of formula I in which Het1 represents the 5-membered ring of a benzimidazole substituted in the 2-position by a N(H)S(O)2R6 group, wherein R6 is as hereinbefore defined, for example under conditions known to those skilled in the art.
6. Compounds of formula I wherein Het1 represents the 5-membered ring of a benzotriazole may be prepared by reaction of a corresponding compound of formula II, as hereinbefore defined, with a suitable source of the nitrosonium cation (e.g. sodium nitrite combined with concentrated HCl), for example at between xe2x88x9210xc2x0 C. and room temperature in the presence of a reaction-inert solvent (e.g. a lower alkyl alcohol such as ethanol).
7. Compounds of formula I wherein Het1 represents the 5-membered ring of an indole may be prepared by cyclisation of a corresponding compound of formula XIV, 
wherein R1, R2, R3 and X are as hereinbefore defined, for example at between room and reflux temperature in the presence of a suitable activator (e.g. copper(I) iodide) and a reaction-inert solvent (e.g. N,N-dimethylformamide).
Compounds of formula XIV may be prepared by reaction of a corresponding compound of formula XV, 
wherein R1, R2, R3, L1 and X are as hereinbefore defined, with acetylene, for example at between room and reflux temperature in the presence of a suitable catalyst system (e.g. bis(triphenylphosphine)palladium(II) chloride combined with copper(I) iodide) and an appropriate organic base (e.g. triethylamine).
Compounds of formula XV in which La represents chloro, bromo or iodo may be prepared by reaction of a corresponding compound of formula V, as hereinbefore defined, with a halogen under conditions known to those skilled in the art (e.g. by reaction with a solution of the halogen in acetic acid).
8. Compounds of formula I wherein Het1 represents the 5-membered ring of a benzoxazole or benzothiazole, optionally substituted in the 2-position by Ta, wherein Ta is as hereinbefore defined, may be prepared by reaction of a corresponding compound of formula XVI, 
wherein E represents OH or SH, and R1, R1, R3 and X are as hereinbefore defined, with a compound of formula III or a compound of formula XII, as hereinbefore defined, for example at between room and reflux temperature in the presence of a reaction-inert solvent (e.g. xylene) and (as appropriate) a suitable catalyst (e.g. pyridinium para-toluenesulfonate) or a suitable base (e.g. triethylamine).
Compounds of formula XVI may be prepared by reduction of a corresponding compound of formula XVII, 
wherein R1, R2, R3, E and X are as hereinbefore defined, under conditions known to those skilled in the art (e.g. under conditions such as those described hereinbefore for the production of compounds of formula II).
Compounds of formula XVII may be prepared by nitration of a corresponding compound of formula XVIII, 
wherein R1, R2, R3, E and X are as hereinbefore defined, for example under nitration conditions known to those skilled in the art (e.g. under conditions such as those described hereinbefore for the production of compounds of formula IV).
9. Compounds of formula I wherein Het1 represents the 5-membered ring of a benzoxazole or benzothiazole, optionally substituted in the 2-position with an OH group, may be prepared by reaction of a corresponding compound of formula XVI, as hereinbefore defined, with a suitable derivative of carbonic acid (e.g. 1,1xe2x80x2-carbonyldiimidazole), for example at between 0xc2x0 C. and reflux temperature in the presence of a reaction-inert solvent (e.g. N,N-dimethylformamide).
10. Compounds of formula I wherein R3 represents C1 alkyl optionally substituted by C3-8 cycloalkyl, Het2, aryl, adamantyl, (which latter two groups are optionally substituted by one or more substituents selected from OH, nitro, amino, halo, CN, CH2CN, CONH2, C1-4 alkyl, C1-4 alkoxy and C1-5 alkanoyl (which latter three groups are optionally substituted by one or more halo atoms)), or R3 represents C2-10 alkyl, C3-10 alkenyl or C3-10 alkynyl (which three groups are all optionally substituted by one or more of the relevant substituents identified hereinbefore in respect to R3), which alkyl, alkenyl or alkynyl groups are attached to the piperidine nitrogen atom via a CH2 group, wherein Het2 is as hereinbefore defined, may be prepared by reduction of a corresponding compound of formula XIX, 
wherein R31 represents H, C3-8 cycloalkyl, Het2, aryl, adamantyl, (which latter two groups are optionally substituted by one or more substituents selected from OH, nitro, amino, halo, CN, CH2CN, CONH2, C1-4 alkyl, C1-4 alkoxy and C1-5 alkanoyl (which latter three groups are optionally substituted by one or more halo atoms)), C1-9 alkyl, C2-9 alkenyl or C2-9 alkynyl, which alkyl, alkenyl or alkynyl groups are optionally substituted and/or terminated by one or more substituents selected from OR8c, S(O)nR8d, CN, halo, C1-6 alkoxy carbonyl, C2-6 alkanoyl, C2-6 alkanoyloxy, C3-8 cycloalkyl, C4-9 cycloalkanoyl, N(R9a)S(O)2R10, Het2, aryl, adamantyl (which latter two groups are optionally substituted by one or more substituents selected from OH, nitro, amino, halo, CN, CH2CN, CONH2, C1-4 alkyl, C1-4 alkoxy and C1-5 alkanoyl (which latter three groups are optionally substituted by one or more halo atoms)), or xe2x80x94Wxe2x80x94A1xe2x80x94N(R9b)(R9c), and R1, R2, R8c, R8d, R9a to R9c, R10, Het1, Het2, n, W, A1, T and X are as hereinbefore defined, using a suitable reducing agent (e.g. lithium aluminium hydride or a borane derivative), for example as described hereinbefore.
Compounds of formula XIX may be prepared by reaction of a corresponding compound of formula XX, 
wherein Het1, R1, R2, T and X are as hereinbefore defined with a compound of formula XXI,
R31CO2Hxe2x80x83xe2x80x83XXI
or a suitable (e.g. carboxylic acid) derivative thereof (e.g. an acid halide or anhydride), wherein R31 is as hereinbefore defined, using coupling conditions known to those skilled in the art.
Compounds of formulae XIX and XX may be prepared from appropriate precursors by analogy with methods disclosed herein that describe the formation of a Het1 group.
11. Compounds of formula I may be prepared by reaction of a corresponding compound of formula XX, as hereinbefore defined, with a compound of formula XI, as hereinbefore defined, under conditions that are known to those skilled in the art, for example as described hereinbefore in respect of the production of compounds of formula VIII.
12. Compounds of formula I wherein R3 represents C1 alkyl, which, in place of being optionally substituted by the substituents as defined hereinbefore, is instead optionally substituted by R31, wherein R31 is as hereinbefore defined, may be prepared by reaction of a corresponding compound of formula XX, as hereinbefore defined, with a compound of formula XXII,
R31CHOxe2x80x83xe2x80x83XXII
wherein R31 is as hereinbefore defined, for example in the presence of a suitable reducing agent (e.g. sodium borohydride, sodium cyano-borohydride or sodium triacetoxyborohydride) and an appropriate solvent (e.g. methanol).
13. Compounds of formula I wherein R3 is a C1-10 alkyl, C4-10 alkenyl or C4-10 alkynyl group that is fully saturated from 1- to 3-C (relative to the piperidine N-atom), and which R3 group is substituted at 2-C (relative to the piperidine N-atom) by S(O)R8d, S(O)2R8d, alkanoyl, cycloalkanoyl, alkoxy carbonyl, CN, xe2x80x94C(O)xe2x80x94A1xe2x80x94N(R9b)(R9c), xe2x80x94(O)xe2x80x94A1xe2x80x94N(R9b)(R9c), or xe2x80x94S(O)2xe2x80x94A1xe2x80x94N(R9b)(R9c), wherein R8d, R9b, R9c and A1 are as hereinbefore defined, may be prepared by reaction of a corresponding compound of formula XX, as hereinbefore defined, with a compound of formula XXIII,
R3axe2x80x94Zxe2x80x83xe2x80x83XXIII
wherein R3a represents R3 as hereinbefore defined except that it does not represent aryl, and that the R3a chain contains an additional carbon-carbon double bond xcex1,xcex2 to the Z-substituent, and Z represents S(O)R8d, S(O)2R8d, alkanoyl, cycloalkanoyl, alkoxy carbonyl, CN, xe2x80x94C(O)xe2x80x94A1xe2x80x94N(R9b)(R9c), xe2x80x94S(O)xe2x80x94A1xe2x80x94N(R9b)(R9c), or xe2x80x94S(O)2xe2x80x94A1xe2x80x94N(R9b)(R9c), wherein R8d, R9b, R9c and A1 are as hereinbefore defined, for example at between room and reflux temperature in the presence of a reaction-inert solvent (e.g. THF).
Compounds of formulae III, IX, X, XI, XII, XIII, XV (in which L1 does not represent chloro, bromo or iodo), XVIII, XXI, XXII, XXIII and derivatives thereof, when not commercially available or not subsequently described, may be obtained either by analogy with the processes described herein, or by conventional synthetic procedures, in accordance with standard techniques, from readily available starting materials using appropriate reagents and reaction conditions.
Compounds of formula I, XIX and XX containing other Het1 rings (in particular, 6- and 7-membered rings) may obtained by analogy with the processes described herein. For example, 7-membered Het1 rings containing 2 nitrogen atoms may be prepared by analogy with process 2 described hereinbefore. Other Het1 rings, for example 7-membered Het1 rings containing 4 nitrogen atoms, may be made by methods known in the art such as those described in Comprehensive Heterocyclic Chemistry II, edited by A R Katritsky, C W Rees and E F V Scriven, 1st Edition, Elsevier Science Ltd. (1996), or by the methods described in The Chemistry of Heterocyclic Compounds, by A Weissberger (John Wiley and Sons), Volumes 5 (1953), 33 (1978) and 50 (1991), the disclosures in which documents are hereby incorporated by reference.
It will be appreciated by those skilled in the art that the compounds delivered by the aforementioned processes can be further modified by interconverting the substituents on the aromatic moieties to other desired substituents (see, for example, Comprehensive Heterocyclic Chemistry II, edited by A R Katritsky, C W Rees and E F V Scriven, 1st Edition, Elsevier Science Ltd. (1996)). For example, nitro may be reduced to amino, OH may be alkylated to give alkoxy, alkoxy may be hydrolysed to OH, alkenes may be hydrogenated to alkanes, halo may be hydrogenated to H, etc. Substituents on alkyl groups in the above-mentioned compounds may also be introduced, removed and interconverted, using techniques which are well known to those skilled in the art.
In some cases it is possible to introduce further substituents into the compounds of formula I directly. For example, chlorination of the phenyl group of compounds of formula I, may be performed by reaction with a solution of chlorine in acetic acid.
The skilled person will also appreciate that these, and other, various standard substituent or functional group interconversions and transformations within certain compounds of formula I will provide other compounds of formula I.
The compounds of the invention may be isolated from their reaction mixtures using conventional techniques.
It will be appreciated by those skilled in the art that, in the course of carrying out the processes described above, the functional groups of intermediate compounds may need to be protected by protecting groups.
Functional groups which it is desirable to protect include oxo, OH, amino and carboxylic acid. Suitable protective groups for oxo include acetals, ketals (e.g. ethylene ketals) and dithianes. Suitable protective groups for OH include trialkylsilyl and diarylalkylsilyl groups (e.g. tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl) and tetrahydropyranyl. Suitable protective groups for amino include tert-butyloxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyloxycarbonyl or ethanoyl. Suitable protective groups for carboxylic acid include C1-6 alkyl or benzyl esters. Suitable protective groups for terminal alkynes include trialkylsilyl and diarylalkylsilyl groups (e.g. tert-butyldimethylsilyl, tert-butyldiphenyl-silyl or trimethylsilyl).
The protection and deprotection of functional groups may take place before or after any of the reaction steps described hereinbefore.
Protective groups may be removed in accordance with techniques which are well known to those skilled in the art.
The use of protecting groups is fully described in xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d, edited by J W F McOmie, Plenum Press (1973), and xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, 2nd edition, T W Greene and P G M Wutz, Wiley-Interscience (1991).
Persons skilled in the art will also appreciate that, in order to obtain compounds of formula I in an alternative, and, on some occasions, more convenient, manner, the individual process steps mentioned hereinbefore may be performed in a different order, and/or the individual reactions may be performed at a different stage in the overall route (i.e. substituents may be added to and/or chemical transformations performed upon, different intermediates to those mentioned hereinbefore in conjunction with a particular reaction). This will depend inter alia on factors such as the nature of other functional groups present in a particular substrate, the availability of key intermediates and the protecting group strategy (if any) to be adopted. Clearly, the type of chemistry involved will influence the choice of reagent that is used in the said synthetic steps, the need, and type, of protecting groups that are employed, and the sequence for accomplishing the synthesis. The procedures may be adapted as appropriate to the reactants, reagents and other reaction parameters in a manner that will be evident to the skilled person by reference to standard textbooks and to the examples provided hereinafter.
It will be appreciated by those skilled in the art that certain protected derivatives of compounds of formula I, which may be made prior to a final deprotection stage, may not possess pharmacological activity as such, but may, in certain instances, be administered orally or parenterally and thereafter metabolised in the body to form compounds of the invention which are pharmacologically active. Such derivatives may therefore be described as xe2x80x9cprodrugsxe2x80x9d. Further, certain compounds of formula I may act as prodrugs of other compounds of formula I.
It will be further appreciated by those skilled in the art, that certain moieties, known to those skilled in the art as xe2x80x9cpro-moietiesxe2x80x9d, for example as described in xe2x80x98Design of Prodrugsxe2x80x99 by H. Bundgaard, Elsevier, 1985 (the disclosure in which document is hereby incorporated by reference), may be placed on appropriate functionalities, when such functionalities are present within compounds of formula I. For example, biolabile groups may be placed on functional groups of compounds of formula I (e.g. an NH functionality in a Het1 group), and in the case of 5- or 6-membered Het1 rings containing NH functionalities, such biolabile derivatives may be preferred.
All protected and biolabile derivatives, and prodrugs, of compounds of formula I are included within the scope of the invention.
Pharmaceutically acceptable acid addition salts of the compounds of formula I which contain a basic centre may be prepared in a conventional manner. For example, a solution of the free base may be treated with the appropriate acid, either neat or in a suitable solvent, and the resulting salt may then be isolated either by filtration of by evaporation under vacuum of the reaction solvent. Pharmaceutically acceptable base addition salts can be obtained in an analogous manner by treating a solution of a compound of formula I with the appropriate base. Both types of salt may be formed or interconverted using ion-exchange resin techniques.
The above procedures may be adapted as appropriate to the particular reactants and groups involved and other variants will be evident to the skilled chemist by reference to standard textbooks and to the examples provided hereafter to enable all of the compounds of formula I to be prepared.
The compounds of the invention are useful because they possess pharmacological activity in animals, especially mammals including humans. They are therefore indicated as pharmaceuticals and, in particular, for use as animal medicaments.
According to a further aspect of the invention there is provided the compounds of the invention for use as medicaments, such as pharmaceuticals and animal medicaments.
By the term xe2x80x9ctreatmentxe2x80x9d, we include both therapeutic (curative) or prophylactic treatment.
In particular, the compounds of the invention have been found to be useful in the treatment of diseases mediated via opiate receptors, which diseases include irritable bowel syndrome; constipation; nausea; vomiting; pruritus; and conditions characterised by pruritus as a symptom.
Thus, according to a further aspect of the invention there is provided the use of the compounds of the invention in the manufacture of a medicament for the treatment of a disease mediated via an opiate receptor. There is further provided the use of the compounds of the invention in the manufacture of a medicament for the treatment of irritable bowel syndrome; constipation; nausea; vomiting; pruritus or a medical condition characterised by pruritus as a symptom.
The compounds of the invention are thus expected to be useful for the curative or prophylactic treatment of pruritic dermatoses including allergic dermatitis and atopy in animals and humans. Other diseases and conditions which may be mentioned include contact dermatitis, psoriasis, eczema and insect bites.
Thus, the invention provides a method of treating or preventing a disease mediated via an opiate receptor. There is further provided a method of treating irritable bowel syndrome; constipation; nausea; vomiting; pruritus or a medical condition characterised by pruritus as a symptom in an animal (e.g. a mammal), which comprises administering a therapeutically effective amount of a compound of the invention to an animal in need of such treatment.
The compounds of the invention will normally be administered orally or by any parenteral route, in the form of pharmaceutical preparations comprising the active ingredient, optionally in the form of a non-toxic organic, or inorganic, acid, or base, addition salt, in a pharmaceutically acceptable dosage form. Depending upon the disorder and patient to be treated, as well as the route of administration, the compositions may be administered at varying doses (see below).
While it is possible to administer a compound of the invention directly without any formulation, the compounds are preferably employed in the form of a pharmaceutical, or veterinary, formulation comprising a pharmaceutically, or veterinarily, acceptable carrier, diluent or excipient and a compound of the invention. The carrier, diluent or excipient may be selected with due regard to the intended route of administration and standard pharmaceutical, and/or veterinary, practice. Pharmaceutical compositions comprising the compounds of the invention may contain from 0.1 percent by weight to 90.0 percent by weight of the active ingredient.
The methods by which the compounds may be administered for veterinary use include oral administration by capsule, bolus, tablet or drench, topical administration as an ointment, a pour-on, spot-on, dip, spray, mousse, shampoo, collar or powder formulation or, alternatively, they can be administered by injection (e.g. subcutaneously, intramuscularly or intravenously), or as an implant. Such formulations may be prepared in a conventional manner in accordance with standard veterinary practice.
The formulations will vary with regard to the weight of active compound contained therein, depending on the species of animal to be treated, the severity and type of infection and the body weight of the animal. For parenteral, topical and oral administration, typical dose ranges of the active ingredient are 0.01 to 100 mg per kg of body weight of the animal. Preferably the range is 0.1 to 10 mg per kg.
The compositions are preferably formulated in a unit dosage form, each dosage containing from about 1 to about 500 mg, more usually about 5 to about 300 mg, of the active ingredient. The term xe2x80x9cunit dosage formxe2x80x9d refers to physically discreet units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier.
In any event, the veterinary practitioner, or the skilled person, will be able to determine the actual dosage which will be most suitable for an individual patient, which may vary with the species, age, weight and response of the particular patient. The above dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
For veterinary use, the compounds of the invention are of particular value for treating pruritus in domestic animals such as cats and dogs and in horses.
As an alternative for treating animals, the compounds may be administered with the animal feedstuff and for this purpose a concentrated feed additive or premix may be prepared for mixing with the normal animal feed.
For human use, the compounds are administered as a pharmaceutical formulation containing the active ingredient together with a pharmaceutically acceptable diluent or carrier. Such compositions include conventional tablet, capsule and ointment preparations which are formulated in accordance with standard pharmaceutical practice.
Compounds of the invention may be administered either alone or in combination with one or more agents used in the treatment or prophylaxis of disease or in the reduction or suppression of symptoms. Examples of such agents (which are provided by way of illustration and should not be construed as limiting) include antiparasitics, e.g. fipronil, lufenuron, imidacloprid, avermectins (e.g. abamectin, ivermectin, doramectin), milbemycins, organophosphates, pyrethroids; antihistamines, e.g. chlorpheniramine, trimeprazine, diphenhydramine, doxylamine; antifungals, e.g. fluconazole, ketoconazole, itraconazole, griseofulvin, amphotericin B; antibacterials, e.g. enroflaxacin, marbofloxacin, ampicillin, amoxycillin; anti-inflammatories e.g. prednisolone, betamethasone, dexamethasone, carprofen, ketoprofen; dietary supplements, e.g. gamma-linoleic acid; and emollients. Therefore, the invention further provides a product containing a compound of the invention and a compound from the above list as a combined preparation for simultaneous, separate or sequential use in the treatment of diseases mediated via opiate receptors.
The skilled person will also appreciate that compounds of the invention may be taken as a single dose on an xe2x80x9cas requiredxe2x80x9d basis (i.e. as needed or desired).
Thus, according to a further aspect of the invention there is provided a pharmaceutical, or veterinary, formulation including a compound of the invention in admixture with a pharmaceutically, or veterinarily, acceptable adjuvant, diluent or carrier.
Compounds of the invention may also have the advantage that, in the treatment of human and/or animal patients, they may be more efficacious than, be less toxic than, have a broader range of activity than, be more potent than, produce fewer side effects than, be more easily absorbed than, or they may have other useful pharmacological properties over, compounds known in the prior art.
The biological activities of the compounds of the present invention were determined by the following test method.
Compounds of the present invention have been found to display activity in binding assays selective for the mu opioid receptor in dog brain. The assays were conducted by the following procedure.
Laboratory bred beagles were used as a source of dog brain tissue. Animals were euthanised, their brains removed and the cerebellum discarded. The remaining brain tissue was sectioned into small pieces approximately 3 g in weight and homogenised in 50 mM Tris pH 7.4 buffer at 4xc2x0 C. using a Kinematica Polytron(trademark) tissue homogeniser. The resulting homogenate was centrifuged at 48,400xc3x97g for 10 minutes and the supernatant discarded. The pellet was resuspended in Tris buffer and incubated at 37xc2x0 C. for 10 minutes. Centrifugation, resuspension and incubation steps were repeated twice more, and the final pellet was resuspended in Tris buffer and stored at xe2x88x9280xc2x0 C. Membrane material prepared in this manner could be stored for up to four weeks prior to use.
For mu assays, increasing concentrations of experimental compound, (5xc3x9710xe2x88x9212 to 10xe2x88x925 M), Tris buffer and 3H ligand, ([D-Ala2,N-Me-Phe4,Gly-ol5]-Enkephalin, DAMGO), were combined in polystyrene tubes. The reaction was initiated by the addition of tissue, and the mixture was incubated at room temperature for 90 minutes. The reaction was terminated by rapid filtration using a Brandel Cell Harvester(trademark) through Betaplate(trademark) GF/A glass fibre filters pre-soaked in 50 mM Tris pH 7.4, 0.1% polyethylenimine buffer. The filters were then washed three times with 0.5 mL ice-cold Tris pH 7.4 buffer. Washed filters were placed in bags and Starscint(trademark) scintillant added. Bags containing the filters and scintillant were heat sealed and counted by a Betaplate(trademark) 1204 beta counter.
Duplicate samples were run for each experimental compound and the data generated was analysed using IC50 analysis software in Graphpad Prism.
Ki values were calculated using Graphpad Prism according to the following formula:
Ki=IC50/1+[3H ligand]/KD
where IC50 is the concentration at which 50% of the 3H ligand is displaced by the test compound and KD is the dissociation constant for the 3H ligand at the receptor site.
The invention is illustrated by the following Examples and Preparations in which the following abbreviations may be used:
APCI=atmospheric pressure chemical ionisation
br (in relation to NMR)=broad
CI=chemical ionisation
DMF=N,N-dimethylformamide
DMSO=dimethylsulfoxide
d (in relation to time)=day
d (in relation to NMR)=doublet
dd (in relation to NMR)=doublet of doublets
EtOAc=ethyl acetate
EtOH=ethanol
h=hour(s)
m (in relation to NMR)=multiplet
MeOH=methanol
min=minute
q (in relation to NMR)=quartet
qi (in relation to NMR)=quintet
s (in relation to NMR)=singlet
t (in relation to NMR)=triplet
THF=tetrahydrofuran
For purifications by HPLC, combination and evaporation of appropriate fractions, determined by analytical HPLC, provided the desired compounds as acetate salts.
Analytical HPLC conditions used to highlight appropriate fractions were Phenomenex Magellanm column, 4.6xc3x97150 mm, packed with 5 xcexc C18 silica, eluting with a gradient of acetonitrile:0.1 M aqueous heptanesulfonic acid (10:90 to 90:10 over 30 min, followed by a further 10 min at 90:10) at 1 mL per minute. Column oven temperature was 40xc2x0 C., and ultraviolet detection of components was made at 220 nM.
When column chromatography is referred to this usually refers to a glass column packed with silica gel (40-63 xcexcm). Pressure of xcx9c165 kPa is generally applied and the ratio of crude product:silica gel required for purification is typically 50:1. Alternatively, an Isolute(trademark) SPE (solid phase extraction) column or Waters Sep-Pak(trademark) cartridge packed with silica gel may be used under atmospheric pressure. The ratio of crude product to silica gel required for purification is typically 100:1.
The hydrochloride salt may be made by methods commonly known to those skilled in the art of synthetic chemistry. Typically, to a solution of free base in dichloromethane (1 g:100 mL) was added ethereal hydrochloric acid (1.0 M, 1.2 equivalent), the excess solvent was decanted off and the remaining precipitate was washed three times with ether and then dried in vacuo.
Nuclear magnetic resonance (NMR) spectral data were obtained using a Brucker AC3000, Brucker AM300, Varian Unity 300 or Varian Unity 400 spectrometer, the observed chemical shifts (xcex4) being consistent with the proposed structures. Mass spectral (MS) data were obtained on a Finnigan Masslab Navigator, a Fisons Instruments Trio 1000, a Fisons Instruments Trio 1000 APCI, or a Micromass Platform LC spectrometer. The calculated and observed ions quoted refer to the isotopic composition of lowest mass. HPLC means high performance liquid chromatography. Room temperature means 20 to 25xc2x0 C.